This invention relates to drug release compositions, and to implantable medical devices that include a surface layer adapted to controllably release a drug in response to sound or thermal energy.
When a biomedical device is implanted into the human body, cells come in contact with the surface of the device and may trigger an adverse foreign body reaction in response to chemical and physical properties of the device surface. Surfaces with defined chemical and physical characteristics are therefore needed to improve the biocompatibility of implanted materials. Moreover, there is a continuing need for drug delivery devices that can be implanted into a living body, such as a mammalian body, and that controllably release one or more drugs within the body. It is particularly desirable that drug delivery devices are capable of delivering several defined drug dosages at desired intervals over a period of days, months or years.
In one embodiment the present invention provides implantable medical devices that possess a surface layer adapted to retain, and controllably release, drug molecules for administration to a subject in need thereof. Biologically active molecules can be covalently attached to the surface layer of some embodiments of the biomedical devices of the invention, for example to reduce or eliminate an adverse foreign body reaction to an implanted medical device, or in any situation where it is desirable to immobilize a molecule, such as a biological polymer, as more fully discussed herein.
In one aspect, the present invention provides biomedical devices comprising: (a) a polymeric or hydrogel substrate; and (b) a surface layer comprising a multiplicity of C10 to C22 unbranched alkyl molecules, wherein: (1) the multiplicity of alkyl molecules define a multiplicity of spaces therebetween; (2) each member of the multiplicity of alkyl molecules possesses a proximal end and a distal end, the proximal end being covalently linked to the substrate; and (3) the surface layer has an ordered state and a less ordered state, the surface layer being reversibly convertible to the less ordered state from the ordered state in response to an effective amount of sound or thermal energy.
In some embodiments, devices of the invention further include drug molecules disposed within the substrate and also disposed in the spaces between the C10 to C22 unbranched alkyl molecules. These embodiments of the devices of the invention are useful, for example, as implantable drug delivery devices.
In other embodiments, the devices of the invention further include a proreactive chemical groups covalently attached to distal ends of the C10 to C22 alkyl molecules. Proreactive chemical groups permits attachment of effector molecules after deblocking of the proreactive chemical group.
In other embodiments, the devices of the invention further include effector molecules covalently attached to distal ends of the C10 to C22 alkyl molecules.
By way of non-limiting example, embodiments of the devices of the invention that include proreactive chemical groups or effector molecules can be utilized in applications where biological signals or trigger molecules are needed at the surface of implanted medical devices to improve tissue healing and biocompatibility.
In another aspect, the present invention provides methods of making a biomedical device, the methods comprising the steps of: (a) disposing a multiplicity of drug molecules within a polymeric or hydrogel substrate; and (b) covalently attaching a multiplicity of C10 to C22 unbranched alkyl molecules to the substrate by forming a covalent linkage between an end group on each member of the multiplicity of C10 to C22 unbranched alkyl molecules and a reactive group on the substrate, thereby forming a surface layer on the substrate wherein: (1) the multiplicity of alkyl molecules define a multiplicity of spaces therebetween; (2) each member of the multiplicity of alkyl molecules possesses a proximal end and a distal end, the proximal end being covalently linked to the substrate; and (3) the surface layer has an ordered state and a less ordered state, the surface layer being reversibly convertible to the less ordered state from the ordered state in response to an effective amount of sound or thermal energy.
In yet another aspect, the present invention provides methods of delivering a drug to a subject, the methods comprising the steps of: (a) introducing into a subject a device comprising: (1) a polymeric or hydrogel substrate comprising a multiplicity of drug molecules; and (2) a surface layer comprising a multiplicity of C10 to C22 unbranched alkyl molecules, wherein: (i) the multiplicity of alkyl molecules define a multiplicity of spaces therebetween; (ii) a multiplicity of drug molecules are disposed within the spaces; (iii) each member of the multiplicity of alkyl molecules possesses a proximal end and a distal end, the proximal end being covalently linked to the substrate; and (iv) the surface layer has an ordered state and a less ordered state, the surface layer being reversibly convertible to the less ordered state from the ordered state in response to an effective amount of sound or thermal energy; and (b) subjecting the device to an amount of sound or thermal energy effective to induce release of the drug molecules from the surface layer.